The immune system functions to protect individuals from infective agents, e.g., bacteria, multi-cellular organisms, and viruses, as well as from cancers. This system includes several types of lymphoid and myeloid cells such as monocytes, macrophages, dendritic cells (DCs), eosinophils, T cells, B cells, and neutrophils. These lymphoid and myeloid cells often produce signaling proteins known as cytokines. The immune response includes inflammation, i.e., the accumulation of immune cells systemically or in a particular location of the body. In response to an infective agent or foreign substance, immune cells secrete cytokines which, in turn, modulate immune cell proliferation, development, differentiation, or migration. Immune response can produce pathological consequences, e.g., when it involves excessive inflammation, as in the autoimmune disorders (see, e.g., Abbas et al. (eds.) (2000) Cellular and Molecular Immunology, W.B. Saunders Co., Philadelphia, Pa.; Oppenheim and Feldmann (eds.) (2001) Cytokine Reference, Academic Press, San Diego, Calif.; von Andrian and Mackay (2000) New Engl. J. Med. 343:1020-1034; Davidson and Diamond (2001) New Engl. J. Med. 345:340-350).
Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Studies have indicated that IL-12 plays a critical role in the differentiation of naïve T cells into T-helper type 1 CD4+ lymphocytes that secrete IFNγ. It has also been shown that IL-12 is essential for T cell dependent immune and inflammatory responses in vivo. See, e.g., Cua et al. (2003) Nature 421:744-748. The IL-12 receptor is composed of IL-12Rβ1 and IL-12Rβ2 subunits.
Interleukin-23 (IL-23) is a heterodimeric cytokine comprised of two subunits, p19 which is unique to IL-23, and p40, which is shared with IL-12. The p19 subunit is structurally related to IL-6, granulocyte-colony stimulating factor (G-CSF), and the p35 subunit of IL-12. IL-23 mediates signaling by binding to a heterodimeric receptor, comprised of IL-23R and IL-12Rβ1, which is shared by the IL-12 receptor. A number of early studies demonstrated that the consequences of a genetic deficiency in p40 (p40 knockout mouse; p40KO mouse) were more severe than those found in a p35KO mouse. Some of these results were eventually explained by the discovery of IL-23, and the finding that the p40KO prevents expression of not only IL-12, but also of IL-23 (see, e.g., Oppmann et al. (2000) Immunity 13:715-725; Wiekowski et al. (2001) J. Immunol. 166:7563-7570; Parham et al. (2002) J. Immunol. 168:5699-708; Frucht (2002) Sci STKE 2002, E1-E3; Elkins et al. (2002) Infection Immunity 70:1936-1948).
Recent studies, through the use of p40 KO mice, have shown that blockade of both IL-23 and IL-12 is an effective treatment for various inflammatory and autoimmune disorders. However, the blockade of IL-12 through p40 appears to have various systemic consequences such as increased susceptibility to opportunistic microbial infections. Bowman et al. (2006) Curr. Opin. Infect. Dis. 19:245.
Therapeutic antibodies may be used to block cytokine activity. Subcutaneous administration is the preferred method of administration of many such antibodies, at least in part because it enables self-administration. Therapeutic antibodies are traditionally prepared in lyophilized form or in solution. Lyophilized forms may exhibit enhanced long-term stability, but require reconstitution prior to use, making them less than ideal for self-administration. Solution formulations do not require reconstitution, but may suffer from reduced stability and typically require cold storage prior to use. Both lyophilized and solution formulations may fail to provide sufficiently high concentrations to allow for high dose delivery by subcutaneous administration. High concentration solution formulations, if achievable, may also be prone to dropping out of solution, or may be too viscous to be delivered in a narrow gauge needle, e.g. as required for subcutaneous administration, particularly self-administration.
Exemplary engineered antibodies to IL-23p19 are disclosed in commonly-assigned U.S. Patent Application Publication Nos. 2010/0272731 and 2010/0111966, in U.S. Patent Application Publication Nos. 2007/0009526 and 2007/0048315, and in International Patent Publication Nos. WO 2007/076524, WO 2007/024846 and WO 2007/147019. One IL-23 antagonist antibody, ustekinumab (STELARA®), is commercially available, but it binds to the p40 subunit of IL-23 rather than the p19 subunit. As a result, ustekinumab also inhibits the activity of IL-12, which is generally an undesired side effect that can lead to increased susceptibility of certain infections and tumors. Bowman et al. (2006) Curr. Opin. Infect. Dis. 19:245. Briakinumab, another anti-p40 antibody that has entered clinical trials, suffers from the same safety concerns. Anti-human IL-23p19 antibody guselkumab (CNTO-1959) has entered clinical trials.
The need exists for improved formulations of anti-huIL-23p19 antibodies for use, e.g., in treatment of inflammatory, autoimmune, and proliferative disorders. Preferably, such antibody formulations will not require reconstitution prior to administration. In addition, such formulations will enable higher concentration administration of the antibody than would be readily achievable using typical solution formulations, and will preferably support high concentrations with sufficiently low viscosity to be conveniently delivered subcutaneously. Such formulations may also provide for sustained release, and will also be more stable than typical solution formulations.